When this project was started initially, live simian immunodeficiency virus (SIV) deleted in the nef gene was felt to be a promising vaccine because it appeared to be attenuated in adult rhesus monkeys, which were protected when challenged with wild-type, nef+ virus. However, when SIVD3, an SIV mutant deleted in the nef gene and in other parts of the virus genome, was given orally to newborn rhesus monkeys, the infants could not suppress virus replication and developed AIDS. From the initial group of 4 monkey infants infected with this virus, 2 have died of AIDS, one is severely immunosuppressed, and the last one has exhibited progressive disease. Thus, SIVD3 is not attentuated in any neonatally exposed animals, and our vaccine project has turned into a pathogenicity study. Our own experiments have confirmed that nef-deleted SIVD3 is attentuated in adult monkeys. Currently, we are studying the host factors that correlate with virulence or attenuation, respectively. Pa rallel studies are ongoing to examine virus factors. We have noticed that the virus undergoes further deletions in most SIVD3-infected monkeys. To test whether the resulting, shortened virus is still replication competent, we cloned the mutated virus directly from the tissues of an infected infant monkey with AIDS. Currently, tests are underway to evaluate the replication competence of the resulting virus. In summary, our studies are designed to identify the factors that determine the outcome of AIDS virus infection - long-term suppression of virus replication versus death from disease. These studies will provide insight into natural host defenses against AIDS viruses.